Process for making spirolactone compounds

ABSTRACT

This invention relates to a process for making spirolactone compounds of general formula I, having an improved IA/IB ratio, according to the following shceme.

BACKGROUND OF THE INVENTION

The present invention relates to a process for the preparation of thespirolactones of formula I.

The compounds of formula I are intermediates useful for the preparationof the spirolactone compounds of formula II.

The compounds of formula II, along with their use as NPY5 antagonistsfor treating bulimia, obesity or diabetes, were disclosed in U.S. Pat.No. 6,335,345, which is incorporated by reference herein in itsentirety, and in WO 01/14376 (published on Mar. 2, 2001). The compoundsof formula II are also useful as agents for the treatment of variousdiseases related to NPY, including, but not limited to, cardiovasculardisorders, such as hypertension, nephropathy, heart disease, vasospasm,arteriosclerosis and the like, central nervous system disorders, such asbulimia, depression, anxiety, seizure, epilepsy, dementia, pain,alcoholism, drug withdrawal and the like, metabolic diseases such asobesity, diabetes, hormone abnormality, hypercholesterolemia,hyperlipidemia and the like, sexual and reproductive dysfunction,gastrointestinal disorder, respiratory disorder, inflammation orglaucoma, and the like.

U.S. Pat. No. 6,335,345 and WO 01/14376, describe a process forpreparing the compounds of formula II from the spirolactone of formulaI.

U.S. Pat. No. 6,388,077 and U.S. Ser. No. 60/352,451 describe processesfor preparing the compounds of formula I. However, a large number ofsynthetic transformations are required (the longest linear sequencebeing about 7 steps) with an overall yield between about 15-20%.

Separation of the cis and trans spirolactone acids IA and IB in theprevious syntheses resulted in the loss of all of the material preparedas the wrong enantiomer. The present invention relates to a process forenriching the trans:cis ratio of the spirolactone acid of formula Icomprising the spirolactone acid mixture, IC, shown on page 3. Theprocess leads to an increase in the amount of trans spirolactone acid IAin the spirolactone acid mixture IC relative to the amount of cisspirolactone acid IB in the spirolactone acid mixture IC. Thisenrichment process leads to a higher yield of the trans spirolactoneacid IA.

Processes for the preparation of organolithium reagents,3-benzylpicolinic and 3-benzylisonicotinic acids, as well as lactonering formation, are described in Synthetic Communications, 20 (17), pp.2623-2629 (1990). Processes for the ortho-lithiation ofN-propenylbenzamides and N-propenyl-o-toluamides are described in J.Org. Chem., vol. 57, pp. 2700-2705 (1992). Reactions of alcohols andketenes to give esters are disclosed in Tidwell, T. T: “Ketenes” JohnWiley & Sons: New York, N.Y., 1995, p. 592-597. The use of hinderedalcohols to de-racemize prochiral carboxylic acids is described inLarsen, R. D. et al., J. Am. Chem. Soc. 1989, 111, 7650; Calmes, M. etal., Tetrahedron: Asymmetry 2002, 13, 293; and Calmes, M. et al.,Tetrahedron, 1997, 40, 13719.

SUMMARY OF THE INVENTION

The present invention provides a process for preparing compounds ofstructural formula I.

The process involves anion formation, such as ortho-lithiation, of anaromatic compound followed by reaction with an ester-substitutedcyclohexanone, hydrolysis and lactone ring formation. The resultingspirolactone acid is converted to an acid halide, which is subsequentlyconverted to a sterically hindered ester via a ketene intermediate. Thesterically hindered ester is hydrolyzed to give the desired spirolactoneof formula IC, predominately in the trans form (IA). Crystallization ofspirolactone IC, or a salt thereof, and separation gives isomers IA andIB, or a salt thereof, in highly pure form.

Individually reacting the separated spirolactones of formula IA or IBwith an amine of the formula H₂NAr¹ gives the corresponding spirolactoneamide IIA or IIB, as shown in general Scheme 1.

In Scheme 1, the reaction of the 4-ester substituted cyclohexanone Bwith the ortho-lithiated aromatic compound A is followed by esterhydrolysis and lactone ring formation to give the spirolactone acid IC,as a mixture with a ratio of approximately 1:1 IA to IB. Thespirolactone acid IC is then activated by conversion to acid halide E,which is subsequently converted to a sterically hindered ester F, via aketene intermediate, by treatment with a sterically hindered alcoholR³OH. The resulting sterically hindered ester F is then hydrolyzed togive spirolactone acid IC, as a mixture of spirolactone acids of formulaIA and IB with a ratio of approximately 80:20 trans (IA) to cis (IB).The mixture of IA and IB may be separated via crystallization bytreatment of the mixture with an acid, to form a salt of IB, andsubsequently separating IA and IB. The trans spirolactone acids IA andIB may then be individually reacted with H₂NAr¹ to give compounds offormula IIA and IIB.

DETAILED DESCRIPTION OF THE INVENTION

By this invention, there is provided a process for the preparation of acompound of structural formula IC, or a salt thereof,

T, U, V and W are each independently selected from the group consistingof:

-   -   (1) nitrogen, and    -   (2) methine,    -   wherein the methine group is unsubstituted or optionally        substituted with a substituent selected from the group        consisting of:        -   (a) halogen,        -   (b) lower alkyl,        -   (c) hydroxy, and        -   (d) lower alkoxy, and            wherein at least two of T, U, V, and W are methine;            comprising the steps of:    -   (a) forming an spirolactone acid halide of formula E    -    wherein X is chlorine or bromine, and T, U, V, and W are as        defined above, by treating the compound of formula IC with a        halogenating agent in a solvent;    -   (b) forming a spirolactone ester of formula P    -    wherein R³ is selected from the group consisting of tert-butyl,        methyl cyclohexyl, methyl cyclopentyl, and neopentyl, and T, U,        V and W are as defined above, by treating the spirolactone acid        halide of formula E with a base and an alcohol in a solvent;    -   (c) forming a spirolactone acid of formula IC    -    wherein T, U, V and W are defined as above, by hydrolyzing the        spirolactone ester of formula F with an aqueous acid; and    -   (d) isolating the resulting product.

In one embodiment of the present invention, the process comprisesincreasing the amount of trans isomer IA

in the compound of structural formula IC

relative to the amount of cis isomer IB

in the compound of structural formula IC,wherein T, U, V and W are each independently selected from the groupconsisting of:

-   -   (1) nitrogen, and    -   (2) methine,    -   wherein the methine group is unsubstituted or optionally        substituted with a substituent selected from the group        consisting of:        -   (a) halogen,        -   (b) lower alkyl,        -   (c) hydroxy, and        -   (d) lower alkoxy, and    -   wherein at least two of T, U, V, and W are methine.

In another embodiment of the present invention, T, V and W are methine,wherein the methine group is unsubstituted or optionally substitutedwith a substituent selected from the group consisting of

-   -   (a) halogen,    -   (b) lower alkyl,    -   (c) hydroxy, and    -   (d) lower alkoxy; and        U is nitrogen.

In a class of this embodiment, T, V and W are unsubstituted methine; andU is nitrogen.

In another embodiment of the present invention, T, U, V and W aremethine, wherein the methine group is unsubstituted or optionallysubstituted with a substituent selected from the group consisting of

-   -   (a) halogen,    -   (b) lower alkyl,    -   (c) hydroxy, and    -   (d) lower alkoxy.

In one class of this embodiment, the methine group is unsubstituted oroptionally substituted with halogen.

In another embodiment of the present invention, the solvent in step (a)is selected from the group consisting of chloroform, ethyl acetate,tetrahydrofuran, dimethoxyethane, diglyme, 2-methyl tetrahydrofuran,1,4-dioxane and diethoxymethane. In a class of this embodiment, thesolvent in step (a) is tetrahydrofuran.

In another embodiment of the present invention, the halogenating agentin step (a) is selected from the group consisting of phosphorusoxychloride, oxalyl chloride, phosphorus trichloride, phosphorustribromide, thionyl chloride, thionyl bromide and oxalyl bromide. In aclass of this embodiment, the halogenating agent in step (a) isphosphorus oxychloride. In a subclass of this class, the amount ofphosphorus oxychloride is between about 0.7 equivalents to about 2.0equivalents relative to spirolactone acid IC. In another subclass ofthis class, the amount of phosphorus oxychloride is about 1.15equivalents relative to spirolactone acid IC. In another subclass ofthis class, the amount of phosphorus oxychloride is about 1.05equivalents relative to spirolactone acid IC.

In another embodiment of the present invention, the spirolactone acidhalide of formula E in step (a) is a spirolactone acid chloride.

In another embodiment of the present invention, the reaction of step (a)further comprises a catalyst. In a class of this embodiment, thecatalyst is dimethyl formamide. In a subclass of this class, the amountof dimethyl formamide is between about 0.2 equivalents to about 5equivalents relative to spirolactone acid of formula IC. In anothersubclass of this class, the amount of dimethyl formamide is about 1equivalent relative to spirolactone acid of formula IC.

In another embodiment of the present invention, the reaction of step (a)is run at a temperature between about 20° C. to about 80° C. In a classof this embodiment, the reaction of step (a) is run at a temperature ofabout 40° C. In a subclass of this class, the reaction of step (a) isrun at a temperature of about 40° C. for about 2 hours.

In another embodiment of the present invention, the base of step (b) isselected from the group consisting ofN,N,N′,N′-tetramethylethylenediamine, triethyl amine,N,N-diisopropylethyl amine, N,N-dimethylethyl amine, pyridine,collidine, 1,8-diazabicyclo[5.4.0]undec-7-ene, N-methylmorpholine, andN,N,N′,N′-tetramethyl-1,6-hexanediamine. In a class of this embodiment,the base of step (b) is N,N,N′,N′-tetramethylethylene-diamine. In asubclass of this class, the amount ofN,N,N′,N′-tetramethylethylene-diamine is between about 1 equivalent toabout 10 equivalents relative to spirolactone ester of formula F. Inanother subclass of this class, the amount ofN,N,N′,N′-tetramethyl-ethylenediamine is about 3.5 equivalents relativeto spirolactone ester of formula F.

In another embodiment of the present invention, the alcohol of step (b)is selected from the group consisting of tert-butyl alcohol, methylcyclohexanol, methyl cyclopentanol, and neopentyl alcohol. In a class ofthis embodiment, the alcohol of step (b) is tert-butyl alcohol. In asubclass of this class, the amount of tert-butyl alcohol is betweenabout 1 equivalent to about 10 equivalents relative to spirolactoneester of formula F. In another subclass of this class, the amount oftert-butyl alcohol is about 1.5 equivalents relative to spirolactoneester of formula F.

In one embodiment of the present invention, the solvent in step (b) isselected from the group consisting of tetrahydrofuran, dimethoxyethane,diglyme, 2-methyl tetrahydrofuran, 1,4-dioxane and diethoxymethane. In aclass of this embodiment, the solvent in step (b) is tetrahydrofuran.

In another embodiment, the reaction of step (b) further comprises asalt. In a class of this embodiment, the salt is selected from the groupconsisting of lithium bromide, lithium chloride, lithium iodide, lithiumperchlorate and lithium tetrafluoroborate. In a subclass of this class,the salt is lithium chloride. In a subclass of this subclass, the amountof lithium chloride is between about 0.5 equivalents to about 5equivalents relative to spirolactone ester of formula F. In anothersubclass of this subclass, the amount of lithium chloride is about 1equivalent relative to spirolactone ester of formula F.

In another embodiment of the present invention, the reaction of step (b)is run at a temperature between about 20° C. to about 80° C. In a classof this embodiment, the reaction of step (b) is run at a temperature ofabout 40° C. In a subclass of this class, the reaction of step (b) isrun at a temperature of about 40° C. for about 2 hours to about 24hours. In another subclass of this class, the reaction of step (b) isrun at a temperature of about 40° C. for about 19 hours.

In another embodiment of the present invention, the aqueous acid of step(c) is selected from the group consisting of sulfuric acid, hydrochloricacid, hydrobromic acid, phosphoric acid and formic acid. In a class ofthis embodiment, the aqueous acid of step (c) is sulfuric acid.

In another embodiment of the present invention, the hydrolysis of step(c) is run at a temperature between about 20° C. and about 100° C. In aclass of this embodiment, the hydrolysis of step (c) is run at atemperature of about 50° C. In a subclass of this class, the hydrolysisof step (c) is run at a temperature of about 50° C. for about 2 hours.

In another embodiment of the present invention, the product of step (d)is isolated by adjusting the pH of the solution of step (c) to betweenabout 0 and 4 with a base and extracting the reaction mixture to affordthe compound IC. In a subclass of this class, the base is sodiumhydroxide. In another subclass, the pH of the solution of step (c) isadjusted to between about 2 to about 3. In a subclass of this subclass,the pH of the solution of step (c) is adjusted to about 2.4.

By this invention, there is further provided a process for thepreparation and separation of a spirolactone of formula IA, or a saltthereof, and a spirolactone of formula IB, or a salt thereof,

T, U, V and W are each independently selected from the group consistingof

-   -   (1) nitrogen, and    -   (2) methine,    -   wherein the methine group is unsubstituted or optionally        substituted with a substituent selected from the group        consisting of        -   (a) halogen,        -   (b) lower alkyl,        -   (c) hydroxy, and        -   (d) lower alkoxy, and            wherein at least two of T, U, V, and W are methine;            comprising the steps of    -   (e) adding a solvent to the compound of formula IC,    -    wherein T, U, V and W are as defined above, to form a mixture;    -   (f) adding an acid to the mixture of step (e) to form a mixture;        and    -   (g) aging the mixture of step (f) for a time and under        conditions effective to afford the compound IA    -   wherein T, U, V and W are as defined above, or a salt thereof.

In one embodiment of the present invention, T, V and W are methine,wherein the methine group is unsubstituted or optionally substitutedwith a substituent selected from the group consisting of

-   -   (a) halogen,    -   (b) lower alkyl,    -   (c) hydroxy, and    -   (d) lower alkoxy; and        U is nitrogen.

In a class of this embodiment, T, V and W are unsubstituted methine; andU is nitrogen.

In another embodiment of the present invention, T, U, V and W aremethine, wherein the methine group is unsubstituted or optionallysubstituted with a substituent selected from the group consisting of

-   -   (a) halogen,    -   (b) lower alkyl,    -   (c) hydroxy, and    -   (d) lower alkoxy.

In one class of this embodiment, the methine group is unsubstituted oroptionally substituted with halogen.

In another embodiment of this invention, the solvent of step (e) isselected from the group consisting of dimethoxyethane, acetonitrile,tetrahydrofuran, or a mixture thereof. In a class of this embodiment,the solvent of step (e) is tetrahydrofuran. In another class of thisembodiment, the solvent of step (e) is acetonitrile.

In another embodiment of this invention, the acid of step (f) isselected from the group consisting of hydrochloric acid, hydrobromicacid, tartaric acid, methane sulfonic acid, toluene sulfonic acid,succinic acid, and sulfuric acid. In a class of this embodiment, theacid of step (f) is hydrochloric acid. In another embodiment of thisinvention, the step (g) is aged at a temperature of about 10° C. to 60°C. In a class of this embodiment, step (g) is aged for a period betweenabout 1 hour to about 48 hours. In a subclass of this class, step (g) isaged at a temperature of about 25° C. for about 3 hours. In anotherembodiment of this invention, the process further comprises step (h) ofisolating the compound of formula IA, or a salt thereof. In a class ofthis embodiment, the compound of formula IA is isolated by filtering andconcentrating the filtrate to give a slurry. In a subclass of thisclass, the slurry is diluted with a solvent and aged for a time andunder conditions to give the compound of formula IA. In another subclassof this class, the slurry is diluted with hexane and aged for about 20hours at about 0° C. In a subclass of this subclass, the compound offormula IA is isolated by filtering the slurry to give the product. Inanother subclass of this class, the slurry is concentrated, diluted withacetonitrile and aged for a time and under conditions to give thecompound of formula IA.

By this invention, there is also provided a process for the preparationof a compound of structural formula IC, or a salt thereof,

T, U, V and W are each independently selected from the group consistingof

-   -   (1) nitrogen, and    -   (2) methine,    -   wherein the methine group is unsubstituted or optionally        substituted with a substituent selected from the group        consisting of        -   (a) halogen,        -   (b) lower alkyl,        -   (c) hydroxy, and        -   (d) lower alkoxy, and            wherein at least two of T, U, V, and W are methine;    -   comprising the steps of    -   (a) combining a strong base with a compound of formula A    -    wherein T, U, V and W are as defined above, in an aprotic        solvent to form a solution;    -   (b) reacting a compound of formula B    -    R² is selected from the group consisting of:        -   (a) lower alkyl, and        -   (b) —CH₂-phenyl, wherein the phenyl group is        -   unsubstituted or substituted with a substituent selected            from the group consisting of            -   (1) lower alkyl,            -   (2) lower alkoxy, and            -   (3) —NO₂,    -    with the solution of step (a) to form an ester of formula C in        solution    -    wherein T, U, V and W are as defined above;    -   (c) adding water to the solution of the ester of formula C in        step (b) to form an acid of formula D    -    wherein T, U, V and W are as defined above;    -   (d) forming a spirolactone acid of formula IC    -    wherein T, U, V, and W are as defined above, by treating the        acid of formula D with an aqueous acid;    -   (e) forming an spirolactone acid halide of formula E    -    wherein X is chlorine or bromine, and T, U, V, and W are as        defined above, by treating the compound of formula IC with a        halogenating agent in a solvent;    -   (f) forming a spirolactone ester of formula F    -    wherein R³ is selected from the group consisting of tert-butyl,        methyl cyclohexyl, methyl cyclopentyl, and neopentyl, and T, U,        V and W are as defined above, by treating the spirolactone acid        halide of formula E with a base and an alcohol in a solvent;    -   (g) forming a spirolactone acid of formula IC    -    wherein T, U, V and W are defined as above, by hydrolyzing the        spirolactone ester of formula F with an aqueous acid; and    -   (h) isolating the resulting product.

In one embodiment of the present invention, the process comprisesincreasing the amount of trans isomer IA

in the compound of structural formula IC

relative to the amount of cis isomer IB

in the compound of structural formula IC,wherein T, U, V and W are each independently selected from the groupconsisting of:

-   -   (1) nitrogen, and    -   (2) methine,    -   wherein the methine group is unsubstituted or optionally        substituted with a substituent selected from the group        consisting of:        -   (a) halogen,        -   (b) lower alkyl,        -   (c) hydroxy, and        -   (d) lower alkoxy, and    -   wherein at least two of T, U, V, and W are methine.

In another embodiment of the present invention, T, V and W are methine,wherein the methine group is unsubstituted or optionally substitutedwith a substituent selected from the group consisting of

-   -   (a) halogen,    -   (b) lower alkyl,    -   (c) hydroxy, and    -   (d) lower alkoxy; and        U is nitrogen.

In a class of this embodiment, T, V and W are unsubstituted methine; andU is nitrogen.

In another embodiment of the present invention, T, U, V and W aremethine, wherein the methine group is unsubstituted or optionallysubstituted with a substituent selected from the group consisting of

-   -   (a) halogen,    -   (b) lower alkyl,    -   (c) hydroxy, and    -   (d) lower alkoxy.

In one class of this embodiment, the methine group is unsubstituted oroptionally substituted with halogen.

In another embodiment of the present invention, steps (a) and (b) arerun at a temperature of between about −50° C. and −80° C. In a class ofthis embodiment, step (a) is aged at a temperature less than about −55°C. In a subclass of this class, step (a) is aged for a period betweenabout 5 minutes to 18 hours.

In another embodiment of this invention, the aprotic solvent of step (a)is selected from the group consisting of tetrahydrofuran, toluene,heptane, dimethoxyethane, benzene, and hexane, diethyl ether, xylene, ora mixture thereof. In a class of this embodiment, the aprotic solvent ofstep (a) is tetrahydrofuran.

In another embodiment of this invention, the strong base of step (a) isselected from the group consisting of n-BuLi, sec-BuLi, t-BuLi, LiHMDS,NaHMDS, KHMDS and LiTMP. In a class of this embodiment, the strong baseof step (a) is n-BuLi.

In another embodiment of this invention, step (a) further comprisesadding a salt selected from the group consisting of LiBr, LiCl, LiI,LiBF₄, LiClO₄, and CeCl₃. In a class of this embodiment, the salt ofstep (a) is LiBr.

In another embodiment of this invention, R² is selected from the groupconsisting of: —CH₃, —CH₂CH₃, —(CH₂)₂CH₃, —CH(CH₃)₂, —(CH₂)₃CH₃, and—CH(CH₃)₃. In a class of this embodiment, R² is —CH₂CH₃.

In another embodiment of the present invention, water is added to thesolution of the ester of formula C in step (c) at a temperature of about60° C. to about −50° C. In a class of this embodiment, water is added ata temperature of about −550° C.

In another embodiment of the present invention, step (c) is run at atemperature between about 0° C. to 50° C. after the addition of water.In a class of this embodiment, step (c) is run at a temperature of about40° C. after the addition of water. In a subclass of this class, step(c) is run for a period between about 1 hour to 4 hours.

In another embodiment of the present invention, the aqueous acid of step(d) is selected from the group consisting of hydrochloric acid, sulfuricacid, methane sulfonic acid, trifluoromethane sulfonic acid, or amixture thereof. In a class of this embodiment, the aqueous acid of step(d) is sulfuric acid. In a subclass of this class, the acid is added ata temperature of about less than 30° C. In another subclass of thisclass, the acid is added at a temperature of about less than 30° C., andaged at a temperature between about 50° C. to about 70° C. for a periodof about 1 hour to about 4 hours. In another embodiment of the presentinvention, the spirolactone acid halide of formula E in step (e) is aspirolactone acid chloride.

In another embodiment of the present invention, the solvent in step (e)is selected from the group consisting of chloroform, ethyl acetate,tetrahydrofuran, dimethoxyethane, diglyme, 2-methyl tetrahydrofuran,1,4-dioxane and diethoxymethane. In a class of this embodiment, thesolvent in step (e) is tetrahydrofuran.

In another embodiment of the present invention, the halogenating agentin step (e) is selected from the group consisting of phosphorusoxychloride, oxalyl chloride, phosphorus trichloride, phosphorustribromide, thionyl chloride, thionyl bromide and oxalyl bromide. In aclass of this embodiment, the halogenating agent in step (e) isphosphorus oxychloride. In a subclass of this class, the amount ofphosphorus oxychloride is between about 0.7 equivalents to about 2.0equivalents relative to spirolactone acid IC. In another subclass ofthis class, the amount of phosphorus oxychloride is about 1.15equivalents relative to spirolactone acid IC. In another subclass ofthis class, the amount of phosphorus oxychloride is about 1.05equivalents relative to spirolactone acid IC.

In another embodiment of the present invention, the reaction of step (e)further comprises a catalyst In a class of this embodiment, the catalystis dimethyl formamide. In a subclass of this class, the amount ofdimethyl formamide is between about 0.2 equivalents to about 5equivalents relative to spirolactone acid of formula IC. In anothersubclass of this class, the amount of dimethyl formamide is about 1equivalent relative to spirolactone acid of formula IC.

In another embodiment of the present invention, the reaction of step (e)is run at a temperature between about 20° C. to about 80° C. In a classof this embodiment, the reaction of step (e) is run at a temperature ofabout 40° C. In a subclass of this class, the reaction of step (e) isrun at a temperature of about 40° C. for about 2 hours.

In another embodiment of the present invention, the base of step (f) isselected from the group consisting ofN,N,N′N′-tetramethylethylenediamine, triethyl amine,N,N-diisopropylethyl amine, N,N-dimethylethyl amine, pyridine,collidine, 1,8-diazabicyclo[5.4.0]undec-7-ene, N-methylmorpholine, andN,N,N′,N′-tetramethyl-1,6-hexanediamine. In a class of this embodiment,the base of step (f) is N,N,N′,N′-tetramethylethylene-diamine. In asubclass of this class, the amount ofN,N,N′,N′-tetramethylethylene-diamine is between about 1 equivalent toabout 10 equivalents relative to spirolactone ester of formula F. Inanother subclass of this class, the amount ofN,N,N′,N′-tetramethylethylene diamine is about 3.5 equivalents relativeto spirolactone ester of formula F.

In another embodiment of the present invention, the alcohol of step (f)is selected from the group consisting of tert-butyl alcohol, methylcyclohexanol, methyl cyclopentanol, and neopentyl alcohol. In a class ofthis embodiment, the alcohol of step (f) is tert-butyl alcohol. In asubclass of this class, the amount of tert-butyl alcohol is betweenabout 1 equivalent to about 10 equivalents relative to spirolactoneester of formula F. In another subclass of this class, the amount oftert-butyl alcohol is about 1.5 equivalents relative to spirolactoneester of formula F.

In one embodiment of the present invention, the solvent in step (f) isselected from the group consisting of tetrahydrofuran, dimethoxyethane,diglyme, 2-methyl tetrahydrofuran, 1,4-dioxane and diethoxymethane. In aclass of this embodiment, the solvent in step (f) is tetrahydrofuran.

In another embodiment, the reaction of step (f) further comprises asalt. In a class of this embodiment, the salt is selected from the groupconsisting of lithium bromide, lithium chloride, lithium iodide, lithiumperchlorate and lithium tetrafluoroborate. In a subclass of this class,the salt is lithium chloride. In a subclass of this subclass, the amountof lithium chloride is between about 0.5 equivalents to about 5equivalents relative to spirolactone ester of formula F. In anothersubclass of this subclass, the amount of lithium chloride is about 1equivalent relative to spirolactone ester of formula F.

In another embodiment of the present invention, the reaction of step (f)is run at a temperature between about 20° C. to about 80° C. In a classof this embodiment, the reaction of step (f) is run at a temperature ofabout 40° C. In a subclass of this class, the reaction of step (f) isrun at a temperature of about 40° C. for about 2 hours to about 24hours. In another subclass of this class, the reaction of step (f) isrun at a temperature of about 40° C. for about 19 hours.

In another embodiment of the present invention, the aqueous acid of step(g) is selected from the group consisting of sulfuric acid, hydrochloricacid, hydrobromic acid, phosphoric acid and formic acid. In a class ofthis embodiment, the aqueous acid of step (g) is sulfuric acid.

In another embodiment of the present invention, the hydrolysis of step(g) is run at a temperature between about 20° C. and about 100° C. In aclass of this embodiment, the hydrolysis of step (g) is run at atemperature of about 50° C. In a subclass of this class, the hydrolysisof step (g) is run at a temperature of about 50° C. for about 2 hours.

In another embodiment of the present invention, the product of step (h)is isolated by adjusting the pH of the solution of step (g) to betweenabout 0 and 4 with a base and extracting the reaction mixture to affordthe compound IC. In a subclass of this class, the base is sodiumhydroxide. In another subclass, the pH of step (g) is adjusted tobetween about about 2 to about 3. In a subclass of this subclass, the pHis adjusted to about 2.4.

By this invention, there is further provided a process for thepreparation and separation of a spirolactone of formula IA, or a saltthereof, and a spirolactone of formula IB, or a salt thereof,

T, U, V and W are each independently selected from the group consistingof

-   -   (1) nitrogen, and    -   (2) methine,    -   wherein the methine group is unsubstituted or optionally        substituted with a substituent selected from the group        consisting of        -   (a) halogen,        -   (b) lower alkyl,        -   (c) hydroxy, and        -   (d) lower alkoxy, and            wherein at least two of T, U, V, and W are methine;            comprising the steps of    -   (i) adding a solvent to the compound of formula IC,    -    wherein T, U, V and W are as defined above, to form a mixture;    -   (j) adding an acid to the mixture of step (i) to form a mixture;        and    -   (k) aging the mixture of step (j) for a time and under        conditions effective to afford the compound IA    -    wherein T, U, V and W are as defined above, or a salt thereof.

In one embodiment of the present invention, T, V and W are methine,wherein the methine group is unsubstituted or optionally substitutedwith a substituent selected from the group consisting of

-   -   (a) halogen,    -   (b) lower alkyl,    -   (c) hydroxy, and    -   (d) lower alkoxy; and        U is nitrogen.

In a class of this embodiment, T, V and W are unsubstituted methine; andU is nitrogen.

In another embodiment of the present invention, T, U, V and W aremethine, wherein the methine group is unsubstituted or optionallysubstituted with a substituent selected from the group consisting of

-   -   (a) halogen,    -   (b) lower alkyl,    -   (c) hydroxy, and    -   (d) lower alkoxy.

In one class of this embodiment, the methine group is unsubstituted oroptionally substituted with halogen.

In another embodiment of this invention, the solvent of step (i) isselected from the group consisting of dimethoxyethane, acetonitrile,tetrahydrofuran, or a mixture thereof. In a class of this embodiment,the solvent of step (i) is tetrahydrofuran. In another class of thisembodiment, the solvent of step (i) is acetonitrile.

In another embodiment of this invention, the acid of step (j) isselected from the group consisting of hydrochloric acid, hydrobromicacid, tartaric acid, methane sulfonic acid, toluene sulfonic acid,succinic acid, and sulfuric acid. In a class of this embodiment, theacid of step (O) is hydrochloric acid.

In another embodiment of this invention, the step (k) is aged at atemperature of about 10° C. to 60° C. In a class of this embodiment,step (k) is aged for a period between about 1 hour to about 48 hours. Ina subclass of this class, step (k) is aged at a temperature of about 25°C. for about 3 hours.

In another embodiment of this invention, the process further comprisesstep (1) of isolating the compound of formula IA, or a salt thereof. Ina class of this embodiment, the compound of formula IA is isolated byfiltering and concentrating the filtrate to give a slurry. In a subclassof this class, the slurry is diluted with a solvent and aged for a timeand under conditions to give the compound of formula IA. In anothersubclass of this class, the slurry is diluted with hexane and aged forabout 20 hours at about 0° C. In a subclass of this subclass, thecompound of formula IA is isolated by filtering the slurry to give theproduct. In another subclass of this class, the slurry is concentrated,diluted with acetonitrile and aged for a time and under conditions togive the compound of formula IA.

In another embodiment of this invention, there is provided a compound ofstructural formula, or a salt thereof,

wherein X is selected from the group consisting of chlorine and bromine,andT, U, V and W are each independently selected from the group consistingof:

-   -   (1) nitrogen, and    -   (2) methine,    -   wherein the methine group is unsubstituted or optionally        substituted with a substituent selected from the group        consisting of:        -   (a) halogen,        -   (b) lower alkyl,        -   (c) hydroxy, and        -   (d) lower alkoxy, and            wherein at least two of T, U, V, and W are methine.

In one class of this embodiment, T, V and W are methine, wherein themethine group is unsubstituted or optionally substituted with asubstituent selected from the group consisting of

-   -   (a) halogen,    -   (b) lower alkyl,    -   (c) hydroxy, and    -   (d) lower alkoxy; and        U is nitrogen.

In a subclass of this class, T, V and W are unsubstituted methine; and Uis nitrogen.

In another class of this embodiment, T, U, V and W are methine, whereinthe methine group is unsubstituted or optionally substituted with asubstituent selected from the group consisting of

-   -   (a) halogen,    -   (b) lower alkyl,    -   (c) hydroxy, and    -   (d) lower alkoxy.

In a subclass of this class, the methine group is unsubstituted oroptionally substituted with halogen.

In another embodiment of this invention, there is provided a compound ofstructural formula

or a salt thereof.

In another embodiment of this invention, there is provided a compositioncomprising about 83% to 52% of compound IA

about 17% to 48% of compound IB

T, U, V and W are each independently selected from the group consistingof:

-   -   (1) nitrogen, and    -   (2) methine,    -   wherein the methine group is unsubstituted or optionally        substituted with a substituent selected from the group        consisting of:        -   (a) halogen,        -   (b) lower alkyl,        -   (c) hydroxy, and        -   (d) lower alkoxy, and            wherein at least two of T, U, V, and W are methine.

In one class of this embodiment, T, V and W are methine, wherein themethine group is unsubstituted or optionally substituted with asubstituent selected from the group consisting of

-   -   (a) halogen,    -   (b) lower alkyl,    -   (c) hydroxy, and    -   (d) lower alkoxy; and        U is nitrogen.

In a subclass of this class, T, V and W are unsubstituted methine; and Uis nitrogen.

In another class of this embodiment, T, U, V and W are methine, whereinthe methine group is unsubstituted or optionally substituted with asubstituent selected from the group consisting of

-   -   (a) halogen,    -   (b) lower alkyl,    -   (c) hydroxy, and    -   (d) lower alkoxy.

In a subclass of this class, the methine group is unsubstituted oroptionally substituted with halogen.

In another embodiment of this invention, there is provided a compositioncomprising about 79% of compound 1-8

about 21% of compound 1-9

In yet another embodiment of this invention, there is provided acomposition comprising about 83% of compound 1-8

about 17% of compound 1-9

As used herein “T, U, V and W” refer to a nitrogen or a methine, whereinthe methine group is unsubstituted or optionally substituted with asubstituent selected from the group consisting of halogen, lower alkyl,hydroxy, and lower alkoxy, and wherein at least two of T, U, V, and Ware methine.

“Methine group is unsubstituted or optionally substituted with asubstituent selected from the group consisting of halogen, lower alkyl,hydroxy and lower alkoxy” refers to unsubstituted methine or methinehaving a substituent which can be selected from the group consisting ofhalogen, lower alkyl, hydroxy and lower alkoxy. The aforesaidsubstituent includes preferably halogen, and the like.

“Halogen” or “halide” refers to fluorine atom, chlorine atom, bromineatom and iodine atom. Halogen atom as the aforesaid substituent includespreferably fluorine atom, chlorine atom, and the like.

“Lower alkyl” refers to a straight- or branched-chain alkyl group of C₁to C₆, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, isohexyl, and the like.Lower alkyl as the aforesaid substituent includes preferably methyl,ethyl, and the like.

“Lower alkoxy” refers to a straight- or branched-chain alkoxy group ofC₁ to C₆, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy,sec-butoxy, isobutoxy, tert-butoxy, pentyloxy, isopentyloxy, hexyloxy,isohexyloxy, and the like. Lower alkoxy as the aforesaid substituentincludes preferably methoxy, ethoxy, and the like.

“Cycloalkyl” refers to a monocyclic saturated carbocyclic ring of C₃ toC₆, wherein one carbocyclic ring carbon is the point of attachment.Examples of cycloalkyl include, but are not limited to, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, and the like.

“Cycloheteroalkyl” refers to a monocyclic saturated ring containing atleast one heteroatom selected from N, S and O of C₃ to C₆, in which thepoint of attachment may be carbon or nitrogen. Examples of“cycloheteroalkyl” include, but are not limited to, pyrrolidinyl,piperidinyl, piperazinyl, imidazolidinyl, tetrahydrofuranyl,morpholinyl, and the like.

“Aryl” refers to a mono- or bicyclic aromatic rings containing onlycarbon atoms. The term also includes aryl group fused to a monocycliccycloalkyl or monocyclic cycloheteroalkyl group in which the point ofattachment is on the aromatic portion. Examples of aryl include phenyl,naphthyl, indanyl, indenyl, tetrahydronaphthyl, 2,3-dihydrobenzofuranyl,dihydrobenzopyranyl, 1,4-benzodioxanyl, and the like. The aryl ring maybe unsubstituted or substituted on one or more carbon atoms.

“Heteroaryl” refers to a mono- or bicyclic aromatic ring, wherein eachring has 5 or 6 carbons, containing at least one heteroatom selectedfrom N, O and S. Examples of heteroaryl include pyrrolyl, isoxazolyl,isothiazolyl, pyrazolyl, pyridyl, oxazolyl, oxadiazolyl, thiadiazolyl,thiazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, triazinyl,thienyl, pyrimidyl, pyridazinyl, pyrazinyl, benzoxazolyl,benzothiazolyl, benzimidazolyl, benzofuranyl, benzothiophenyl,furo(2,3-b)pyridyl, quinolyl, indolyl, isoquinolyl, and the like. Theheteroaryl ring may be unsubstituted or substituted on one or morecarbon atoms.

As used herein, the term “anion” refers to a mono-anion or a di-anion.

The compounds in the processes of the present invention includestereoisomers, diastereomers and geometerical isomers, or tautomersdepending on the mode of substitution. The compounds may contain one ormore chiral centers and occur as racemates, racemic mixtures and asindividual diastereomers, diastereomeric mixtures, enantiomeric mixturesor single enantiomers, or tautomers. The present invention is meant tocomprehend all such isomeric forms of the compounds in the compositionsof the present invention, and their mixtures. Therefore, where acompound is chiral, the separate enantiomers, and diastereomers,substantially free of the other, are included within the scope of theinvention; further included are all mixtures of enantiomers, and all ofthe mixtures of diastereomers. Also included within the scope of theinvention are salts, polymorphs, hydrates and solvates of the compoundsand intermediates of the instant invention.

Compounds of the structural formula I and structural formula II includestereoisomers, such as the trans-form of compounds of the generalformulas IA and IIA:

and the cis-form compounds of the general formula IB and IIB:

The trans form is preferred.

The salts of compounds of formula I, IA, IB, and IC refer to thepharmaceutically acceptable and common salts, for example, base additionsalt to carboxyl group when the compound has a carboxyl group, or acidaddition salt to amino or basic cycloheteroalkyl when the compound hasan amino or basic cycloheteroalkyl group, and the like.

The base addition salts include salts with alkali metals (including, butnot limited to, sodium, potassium); alkaline earth metals (including,but not limited to, calcium, magnesium); ammonium or organic amines(including, but not limited to, trimethylamine, triethylamine,dicyclohexylamine, ethanolamine, diethanolamine, triethanolamine,procaine, N,N′-dibenzylethylenediamine), and the like.

The acid addition salts include salts with inorganic acids (including,but not limited to, hydrochloric acid, sulfuric acid, nitric acid,phosphoric acid, perchloric acid), organic acids (including, but notlimited to, maleic acid, fumaric acid, tartaric acid, citric acid,ascorbic acid, trriluoroacetic acid, acetic acid), sulfonic acids(including, but not limited to, methanesulfonic acid, isethionic acid,benzenesulfonic acid, p-toluenesulfonic acid, p-toluenesulfonic acidmonohydrate, p-toluene sulfonic acid hydrate, camphor sulfonic acid),and the like.

In the schemes and examples below, various reagent symbols andabbreviations have the following meanings:

-   -   n-BuLi or BuLi: n-butyl lithium    -   sec-BuLi: sec-butyl lithium    -   t-BuLi: tert-butyl lithium    -   t-BuOH: tert-butyl alcohol    -   DBU: 1,8-diazabicyclo[5.4.0]undec-7-ene    -   DMF: dimethyl formamide    -   DMSO: dimethyl sulfoxide    -   -Et: —CH₂CH₃    -   g: grams    -   h: hours    -   HCl: hydrochloric acid    -   H₂SO₄: sulfuric acid    -   KHMDS: potassium hexamethyl disilazide    -   LiBr: lithium bromide    -   LiCl: lithium chloride    -   LiHMDS: lithium hexamethyl disilazide    -   LiTMP: lithium tetramethyl piperadide    -   NaHMDS: sodium hexamethyl disilazide    -   -Me: methyl    -   mL: milliliter    -   mmol: millimole    -   mol: moles/liter    -   POCl₃: phosphorus oxychloride    -   THF: tetrahydrofuran    -   TMEDA tetramethylethylenediamine or        N,N,N′,N′-tetramethylethylenediamine

The compounds of the present invention can be prepared by employing thegeneral process in Scheme 1. The novel process of the present inventioncan be exemplified in Scheme 2, which illustrates the preparation of thespirolactones of structural formula I, IA, IB and IC, and salts thereof.The salts of IA and IB may be separated and individually reacted with anamine, H₂NAr¹. For example, the neutralization, activation andsubsequent reaction of the salt of IA with H₂NAr¹ yields compounds offormula II.

In Scheme 2, the 4-ethyl ester substituted cyclohexanone is converted tothe carboxylic acid before ring lactonization to form the spirolactoneIC, via intermediate C. Isonicotinamide 1-1 is deprotonated with a base,such as n-butyllithium, in the presence of a salt, such as LiBr, in asolvent such as THF, and at a temperature between about −55° C. to −65°C., to form a metallated anilide. The metallated anilide is added to asolution of ethyl 4-oxocyclohexanecarboxylate 1-2 in a solvent such asTHF, at a temperature below about −55° C., followed by the addition ofwater to form the diacid 1-3. The diacid 1-3 is then treated with anaqueous acid, such as sulfuric acid, at a temperature below about 30°C., to form the lactone ring of spirolactone acid 14, as a mixture ofabout 1:1 cis to trans spirolactone acids. Spirolactone acid 14 is thenactivated by forming an acid halide 1-5, by treatment with ahalogenating agent in a solvent such as THF in the presence of DMF. Theacid halide is preferentially an acid chloride formed by treatment ofthe acid with phosphorus oxychloride. The acid chloride 1-5 is treatedwith a base such as N,N,N′,N-tetramethylethylenediamine, in the presenceof an alcohol, such as tert-butanol, and a salt, such as LiCl, in asolvent such as THF, to form an ester 1-6 via a ketene intermediate. Theester 1-6 is subsequently hydrolyzed with an aqueous acid, such asaqueous sulfuric acid, at a temperature of about 50° C., to form acid1-7 (IC) as a 80:20 trans/cis mixture. The acid 1-7 may be furtherpurified and separated into acids 1-8 (IA, trans) and 1-9 (IB, cis) byforming a salt of 1-9 with an acid, such as hydrochloric acid, andseparating the compounds by recrystallizing from a solvent such asacetonitrile, tetrahydrofuran, heptane or a mixture thereof. Thisprocess provides IA substantially free from IIB and provides IBsubstantially free from IA.

The following examples are provided to illustrate the invention and arenot to be construed as limiting the scope of the invention in anymanner.

EXAMPLE 1 Preparation ofTrans-1′-oxospiro[cyclohexane-1,3′(1′H)-furo[3,4-C]pyridine]-4-carboxylicacid, 1-5, (Method A)

Step A: Preparation of Compound 1-3

The isonicotinamide 1-1 (100 g, 0.50 mol, Kingchem), THF (0.5 L) and a 1M LiBr solution (prepared by dissolving 1.50 mol of LiBr in 1.5 L ofTHF) were mixed in a flask. The resulting solution was degassed withnitrogen and cooled to −65° C. n-BuLi (1.56 M in hexane; 666 mL, 1.04mol) was then added while maintaining the batch temperature below −55°C. The resulting solution was then aged at a temperature less than −55°C. for a period between 1 to 7 hours to give a metalated anilidemixture.

A solution of ethyl 4-oxocyclohexanecarboxylate 1-2 (100 mL, 0.63 mol,EMS Dottikon AG) in THF (1 L) was cooled in a separate flask to atemperature below −60° C. To the solution was added the above metalatedanilide mixture, while maintaining the batch temperature below −55° C.The resulting solution was aged at a temperature below −55° C. for 1hour and then carefully quenched into H₂O (1 L). The resulting mixturewas warmed to 40° C. and aged at 40° C. for a period between 1 to 4hours. After cooling to room temperature, the organic layer was removedand the aqueous layer (1.3 L; pH ˜11) was washed with THF (1 L) to givean aqueous solution of the diacid 1-3.Step B: Preparation of Compound 1-4

To the aqueous solution of the diacid 1-3 from Step A was added H₂O (500mL, 5 mL/g of anilide) and 47% aqueous H₂SO₄ to adjust to pH 2-3,maintaining the temperature below 30° C. The resulting white suspensionwas aged at a temperature of 30° C.-70° C. for a period of 1 to 4 hours.After cooling the batch, THF (2500 mL) and 20% aqueous NaCl (600 ml)were added to extract the product acid 1-4. After the separation of thetwo layers, the water layer was re-extracted with THF (1000 mL). Thecombined THF extracts (3500 mL) were concentrated to 1250 mL. Themixture turned to a suspension of spirolactone acid 1-4 during thedistillation.

Selected Signals: ¹H NMR (300.13 MHz, DMSO-d₆): Λ 12.31 (br, 1H), 9.10(d, 1H), 8.85 (m, 1H), 7.82 (m, 1H). 2.70 (m, 0.45H), 2.43 (m, 0.55H),1.65-2.25 (m, 8H).Step C: Preparation of Compound 1-7

Spirolactone acid 1-4 (800 g of a 55 A % cis:45 A % trans mixture) wasadded to a 50 L vessel containing THF (17.6 L). The slurry was treatedwith DMF (260 mL, 3.2 mol) and then at 22° C., with POCl₃ (350 mL) over10 min to form the acid chloride 1-5. The solution was warmed to 40° C.over 45 min, aged for 2 h and then cooled to 24° C. In a separate 12 Lflask was sequentially added: THF (3.3 L), TMEDA (1.7 L), t-butanol (465mL) and LiCl (143 g). After aging at 25° C. for 1 h, this resultingsolution was added to the solution of acid chloride 1-5 at 24-30° C.over 25 min and aged for 19 h at 35-39° C. The reaction mixture wascooled to 0° C. and quenched by adding 4.2 L 33% H₂SO₄ slowly over 20min during which time the internal temperature rose to 22° C. Theresulting solution was heated to 50° C. for 3 h. The solution was thencooled to 22° C. and pH adjusted to 2.4 with 6 N NaOH (7.0 kg). Theorganic layer was separated and washed with 2×8 L of aqueous HCl/NaCl(pH 2.5). THF (3.3 L) was added to the organic layer to raise thesolution volume to about 26 L and it was charged to a 50 L flask. Theorganic layer was azeotropically dried via a constant volumedistillation at atmospheric pressure until the KF was 0.3%. (Utilizedabout 51 kg THF) to provide a solution of spirolactone acid 1-7.Step D: Separation of Compound 1-7 into Compounds 1-8 and 1-9

The solution of spirolactone 1-7 was cooled to 22° C. and concentratedHCl (60 mL) was slowly added to the solution. The resulting slurry wasaged at 25° C. for 3 h, and the precipitate was removed via filtrationand washed with THF (1×1 L). The filtrate containing spirolactone acid1-8 was concentrated to 6.5 L in vacuo (internal temp=38-42° C.), andthe resulting slurry was cooled to 22° C. over 1 h and aged for 1 h.Heptane (6 L) was added over 2 h and the slurry was cooled 0° C. andaged for 20 h, followed by vacuum filtration, rinsing the product cakewith THF-heptane (2/3; 2×600 mL) and drying in vacuo at 45° C. toprovide the spirolactone acid 1-8.

¹H NMR (400.13 MHz; DMSO-d₆): A 12.34 (br, 1H), 9.04 (d, J=1.0 Hz, 1H),8.85 (d, J=5.0 Hz, 1H), 7.82 (dd, J=5.0 Hz, 1.0 Hz, 1H), 2.70 (br m,1H), 2.08-1.89 (overlapping m, 6H), 1.82-1.76 (overlapping m, 2H).

¹³C NMR (100.62 MHz; DMSO-d₆): 175.9, 167.9, 150.6, 147.5, 144.9, 133.1,119.1, 87.2, 38.1, 33.1, 23.9.

Alternatively, spirolactone 1-8 may be crystallized from acetonitrileaccording to the following procedure. The filtrate containingspirolactone acid 1-8 in step D (250 ml; 15 g/L trans Acid) wasconcentrated to 44 ml via distillation and cooled to 40° C. Acetonitrile(7.5 mL) was added with 50 mg seed. The slurry was aged at 40° C. for2.5 h, cooled to 22° C. and aged for 2 h. The remaining THF was removedby a constant volume distillation feeding in acetonitrile until the THFlevel was <2 A %. The batch was cooled to 0° C. and aged for 2 hoursprior to filtration, then washed with chilled acetonitrile (1×10 mL),and dried in vacuo to give spirolactone acid 1-8.

While the invention has been described and illustrated with reference tocertain particular embodiments thereof, those skilled in the art willappreciate that various changes, modifications and substitutions can bemade therein without departing from the spirit and scope of theinvention. It is intended, therefore, that the invention be defined bythe scope of the claims which follow and that such claims be interpretedas broadly as is reasonable.

1. A process for preparing a compound of the formula IC, or a saltthereof,

T, U, V and W are each independently selected from the group consistingof: (1) nitrogen, and (2) methine,  wherein the methine group isunsubstituted or optionally substituted with a substituent selected fromthe group consisting of: (a) halogen, (b) lower alkyl, (c) hydroxy, and(d) lower alkoxy, and wherein at least two of T, U, V, and W aremethine; comprising the steps of: (a) forming an spirolactone acidhalide of formula E

 wherein X is chlorine or bromine, and T, U, V, and W are as definedabove, by treating the compound of formula IC with a halogenating agentin a solvent; (b) forming a spirolactone ester of formula F

 wherein R³ is selected from the group consisting of tert-butyl, methylcyclohexyl, methyl cyclopentyl, and neopentyl, and T, U, V and W are asdefined above, by treating the spirolactone acid halide of formula Ewith a base and an alcohol in a solvent; (c) forming a spirolactone acidof formula IC

 wherein T, U, V and W are defined as above, by hydrolyzing thespirolactone ester of formula F with an aqueous acid; and (d) isolatingthe resulting product.
 2. The process of claim 1 wherein the solvent ofstep (a) is selected from the group consisting of chloroform, ethylacetate, tetrahydrofuran, dimethoxyethane, diglyme, 2-methyltetrahydrofuran, 1,4-dioxane and diethoxymethane.
 3. The process ofclaim 2 wherein the solvent of step (a) is tetrahydrofuran.
 4. Theprocess of claim 1 wherein the halogenating agent in step (a) isselected from the group consisting of phosphorus oxychloride, oxalylchloride, phosphorus trichloride, phosphorus tribromide, thionylchloride, thionyl bromide and oxalyl bromide.
 5. The process of claim 4wherein the halogenating agent in step (a) is phosphorus oxychloride. 6.The process of claim 1 wherein the spirolactone acid halide of formula Ein step (a) is a spirolactone acid chloride.
 7. The process of claim 1wherein step (a) further comprises a catalyst.
 8. The process of claim 7wherein the catalyst of step (a) is dimethyl formamide.
 9. The processof claim 1 wherein the base of step (b) is selected from the groupconsisting of N,N,N′,N′-tetramethylethylenediamine, triethyl amine,N,N-diisopropylethyl amine, N,N-dimethylethyl amine, pyridine,collidine, 1,8-diazabicyclo[5.4.0]undec-7-ene, N-methylmorpholine, andN,N,N′,N′-tetramethyl-1,6-hexanediamine.
 10. The process of claim 9wherein the base of step (b) is N,N,N′,N′-tetramethylethylenediamine.11. The process of claim 1 wherein the alcohol of step (b) is selectedfrom the group consisting of tert-butyl alcohol, methyl cyclohexanol,methyl cyclopentanol, and neopentyl alcohol.
 12. The process of claim 11wherein the alcohol of step (b) is tert-butyl alcohol.
 13. The processof claim 1 wherein the solvent in step (b) is selected from the groupconsisting of tetrahydrofuran, dimethoxyethane, diglyme, 2-methyltetrahydrofuran, 1,4-dioxane and diethoxymethane.
 14. The process ofclaim 13 wherein the solvent in step (b) is tetrahydrofuran.
 15. Theprocess of claim 1 wherein step (b) further comprises a salt.
 16. Theprocess of claim 15 wherein the salt of step (b) is selected from thegroup consisting of lithium bromide, lithium chloride, lithium iodide,lithium perchlorate and lithium tetrafluoroborate.
 17. The process ofclaim 16 wherein the salt of step (b) is lithium chloride.
 18. Theprocess of claim 1 wherein the aqueous acid of step (c) is selected fromthe group consisting of sulfuric acid, hydrochloric acid, hydrobromicacid, phosphoric acid and formic acid.
 19. The process of claim 18wherein the aqueous acid of step (c) is is sulfuric acid.
 20. Theprocess of claim 1 further comprising the steps of (e) adding a solventto the compound of formula IC,

wherein T, U, V and W are as defined above, to form a mixture; (f)adding an acid to the mixture of step (e) to form a mixture; and (g)aging the mixture of step (f) for a time and under conditions effectiveto afford the compound IA

wherein T, U, V and W are as defined above, or a salt thereof.
 21. Theprocess of claim 20 wherein the solvent of step (e) is selected from thegroup consisting of dimethoxyethane, acetonitrile, tetrahydrofuran, or amixture thereof.
 22. The process of claim 21 wherein the solvent of step(e) is tetrahydrofuran.
 23. The process of claim 20, wherein the acid ofstep (f) is selected from the group consisting of hydrochloric acid,hydrobromic acid, tartaric acid, methane sulfonic acid, toluene sulfonicacid, succinic acid, and sulfuric acid.
 24. The process of claim 23wherein the acid of step (f) is hydrochloric acid.
 25. The process ofclaim 20, wherein step (g) is aged at a temperature of about 10° C. to60° C.
 26. The process of claim 25, wherein step (g) is aged at atemperature of about 25° C. for about 3 hours.
 27. The process of claim20 further comprising the step (h) of isolating the compound of formulaIA, or a salt thereof.
 28. The process of claim 1 wherein T, V and W aremethine, wherein the methine group is unsubstituted or optionallysubstituted with a substituent selected from the group consisting of (a)halogen, (b) lower alkyl, (c) hydroxy, and (d) lower alkoxy; and U isnitrogen.
 29. The process of claim 29 wherein T, V and W areunsubstituted methine; and U is nitrogen.
 30. The process of claim 1wherein T, U, V and W are methine, wherein the methine group isunsubstituted or optionally substituted with a substituent selected fromthe group consisting of (a) halogen, (b) lower alkyl, (c) hydroxy, and(d) lower alkoxy.
 31. The process of claim 1 wherein the amount of transisomer IA

in the compound of structural formula IC

is increased relative to the amount of cis isomer IB

in the compound of structural formula IC, wherein T, U, V and W are eachindependently selected from the group consisting of: (1) nitrogen, and(2) methine,  wherein the methine group is unsubstituted or optionallysubstituted with a substituent selected from the group consisting of:(a) halogen, (b) lower alkyl, (c) hydroxy, and (d) lower alkoxy, and wherein at least two of T, U, V, and W are methine.
 32. A compositioncomprising about 83% to 52% of compound IA

about 17% to 48% of compound IB

wherein T, U, V and W are each independently selected from the groupconsisting of: (1) nitrogen, and (2) methine,  wherein the methine groupis unsubstituted or optionally substituted with a substituent selectedfrom the group consisting of: (a) halogen, (b) lower alkyl, (c) hydroxy,and (d) lower alkoxy, and wherein at least two of T, U, V, and W aremethine.
 33. The composition of claim 32 comprising about 79% ofcompound 1-8

about 21% of compound 1-9


34. The composition of claim 32 comprising about 83% of compound 1-8

about 17% of compound 1-9